CT-1 (Cardiotrophin-1)-Gal-3 (Galectin-3) Axis in Cardiac Fibrosis and Inflammation

Abstract

Myocardial fibrosis is a main contributor to the development of heart failure (HF). CT-1 (cardiotrophin-1) and Gal-3 (galectin-3) are increased in HF and associated with myocardial fibrosis. The aim of this study is to analyze whether CT-1 regulates Gal-3. Proteomic analysis revealed that Gal-3 was upregulated by CT-1 in human cardiac fibroblasts in parallel with other profibrotic and proinflammatory markers. CT-1 upregulation of Gal-3 was mediated by ERK (extracellular signal-regulated kinase) 1/2 and Stat-3 (signal transducer and activator of transcription 3) pathways. Male Wistar rats and B6CBAF1 mice treated with CT-1 (20 µg/kg per day) presented higher cardiac Gal-3 levels and myocardial fibrosis. In CT-1–treated rats, direct correlations were found between cardiac CT-1 and Gal-3 levels, as well as between Gal-3 and perivascular fibrosis. Gal-3 genetic disruption in human cardiac fibroblasts and pharmacological Gal-3 inhibition in mice prevented the profibrotic and proinflammatory effects of CT-1. Dahl salt-sensitive hypertensive rats with diastolic dysfunction showed increased cardiac CT-1 and Gal-3 expression together with cardiac fibrosis and inflammation. CT-1 and Gal-3 directly correlated with myocardial fibrosis. In HF patients, myocardial and plasma CT-1 and Gal-3 were increased and directly correlated. In addition, HF patients with high CT-1 and Gal-3 plasma levels presented an increased risk of cardiovascular death. Our data suggest that CT-1 upregulates Gal-3 which, in turn, mediates the proinflammatory and profibrotic myocardial effects of CT-1. The elevation of both molecules in HF patients identifies a subgroup of patients with a higher risk of cardiovascular mortality. The CT-1/Gal-3 axis emerges as a candidate therapeutic target and a potential prognostic biomarker in HF.

Interleukin-1 Receptor Antagonist Protects Newborn Mice Against Pulmonary Hypertension

“…In addition, we assessed changes in the expression of markers of cardiac inflammation and fibrotic remodeling by RT-PCR. Lgals3 , which encodes the protein Mac-2/galectin-3, is predominantly expressed by activated macrophages and known to regulate inflammatory and fibrotic responses in the heart (48), was markedly increased (2.9-fold) by exposure to hyperoxia when compared to air vehicle. This increase was reduced by 50% in daily IL-1Ra-treated hyperoxic mice (Figure 6C).…”

Biomarkers of Inflammation in Left Ventricular Diastolic Dysfunction

“…Martínez-Martínez et al found in a study completed on Wistar rats that once treated with CT-1, they presented a higher cardiac Gal-3 level and a higher degree of myocardial fibrosis and also perivascular fibrosis. They concluded that an elevation of both molecules in HF patients could mean higher cardiovascular mortality and that the axes CT-1/Gal-3 might become a therapeutic target and also a HF biomarker [76]. Other data suggests that Gal-3 could also enhance a pathway through myocardial fibrosis, by activating RAAS.…”

N-acetyl Cysteine Can Blunt Metabolic and Cardiovascular Effects via Down-regulation of Cardiotrophin-1 in Rat Model of Fructose-induced Metabolic Syndrome

“…The aortic stiffness reported in MS may be ascribed to thoracic aorta perivascular adipose tissue dysfunction observed in MS that through interplay between TNFα and NADPH-oxidase 2 causing aortic stiffness [64]. Also, Martinez-Martinez [65] observed that CT-1 could up-regulate cardiac galectin-3 which, in turn, mediates the proin ammatory and pro brotic myocardial effects of CT-1.…”